A hybrid polymer to target blood group dependence of cholera toxin.

Cholera is a potentially fatal bacterial infection caused by the cholera toxin (CT), an AB5 toxin secreted by Vibrio cholera. GM1 has long been known as the receptor of the cholera toxin in the intestine. However, increasing evidence is pointing towards the role of fucosylated conjugates as additional attachment options of the toxin. In the present paper we have synthesized a polymeric hybrid which can inhibit both modes of attachment.

Orthoester functionalized N-guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of ß-glucocerebrosidase.

Alkylated guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol bearing an orthoester moiety were prepared using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that one of the compounds prepared displays potent inhibition against human ß-glucocerebrosidase (GBA) at pH 7.0 with IC50 values in the low nanomolar range. Notably, a significant drop in inhibitory activity is observed when the same compound is tested at pH 5.2. This pH sensitive activity is due to degradation of the orthoester functionality at lower pH accompanied by loss of the alkyl group. This approach provides a degree of control in tuning enzyme inhibition based on the local pH. Compounds like those here described may serve as tools for studying various lysosomal storage disorders such as Gaucher disease. In this regard, the most active compound was also evaluated as a potential pharmacological chaperone by assessing its effect on GBA activity in an assay employing fibroblasts from Gaucher patients.

Bicyclic isoureas derived from 1-deoxynojirimycin are potent inhibitors of ß-glucocerebrosidase.

A series of bicyclic isourea derivatives were prepared from 1-deoxynojirimycin using a concise synthetic protocol proceeding via a guanidino intermediate. Inhibition assays with a panel of glycosidases revealed that these deoxynojirimycin-derived bicyclic isoureas display very potent inhibition against human recombinant ß-glucocerebrosidase with IC50 values in the low nanomolar range.

Functional Characterization of Cholera Toxin Inhibitors Using Human Intestinal Organoids.

Preclinical drug testing in primary human cell models that recapitulate disease can significantly reduce animal experimentation and time-to-the-clinic. We used intestinal organoids to quantitatively study the potency of multivalent cholera toxin inhibitors. The method enabled the determination of IC50 values over a wide range of potencies (15 pM to 9 mM). The results indicate for the first time that an organoid-based swelling assay is a useful preclinical method to evaluate inhibitor potencies of drugs that target pathogen-derived toxins.

Head-to-Head Comparison of Anti-Inflammatory Performance of Known Natural Products In Vitro.

Inflammation is an important therapeutic target. Due to their potency, steroidal drugs dominate the current treatment of inflammatory disorders. However, steroidal drugs can also exert a broad range of side effects and appear not always effective. This calls for the development of alternative drugs with a different mechanism of action, which are likely to be found in the field of natural products (NPs). For many NPs strong anti-inflammatory effects have been described, but usually investigating a single compound in a single assay. In this study, eight promising NPs were selected and tested against the strong anti-inflammatory drug prednisolone. For this head-to-head comparison, in vitro assays were used which represent different pathways of the inflammatory response: TNF-α and IL-6 expression by macrophages, IL-8 expression by colon epithelial cells, ROS production in polymorphonuclear leukocytes and platelet activation in whole blood. Performance profiles were established which allowed us to identify curcumin, berberine chloride and epigallocatechin gallate as potential alternatives for prednisolone or other glucocorticoids in inflammation.

Oseltamivir analogues bearing N-substituted guanidines as potent neuraminidase inhibitors.

A series of oseltamivir analogues bearing an N-substituted guanidine unit were prepared and evaluated as inhibitors of neuraminidases from four strains of influenza. The two most potent analogues identified contain relatively small N-guanidine substituents (N-methyl and N-hydroxyl) and display enhanced inhibition with IC50 values in the low nanomolar range against neuraminidases from wild-type and oseltamivir-resistant strains. Potential advantages of including the N-hydroxyguanidine moiety in neuraminidase inhibitors are also discussed.

Bioactive constituents of Cedrelopsis microfoliata.

The stem bark of Cedrelopsis microfoliata has yielded the new compounds microfolian (1), microfolione (2), and microfolicoumarin (6) along with the known compounds agrandol (3), cedrecoumarin A (4), obliquin (5), and sesquichamaenol (7). Compounds 2-4 were found to show agonistic activity on both alpha- and beta-estrogenic receptors, and compounds 1, 3, and 4 were shown to inhibit the chemiluminescence of reactive oxygen metabolites and showed superoxide scavenging activity.